This invention relates to methods for treating oophorectomized women or women with other forms of ovarian failure, as well as to formulations for use in such methods. More particularly, the present invention is directed to methods and preparations effective for extended periods of time in preventing adverse symptoms associated with the loss of ovarian function in oophorectomized women or women with other forms of ovarian failure.
Oophorectomy and salpingo-oophorectomy are frequently performed in the United States, alone or with a hysterectomy. The most common indication is the treatment of uterine fibroids; other indications include malignancy and other benign gynecological disorders. In 1984, there were 498,000 such procedures performed in the U.S. As a consequence of oophorectomy, there is a marked reduction in serum estradiol and serum testosterone levels. Common side effects reported to occur as a result of these reductions in serum hormone levels after oophorectomy include: hot flashes, vaginal dryness and bone loss. Additional side effects that have been reported in some patients include: sweating, headache, depression, lability in mood, nausea and/or vomiting, nervousness, insomnia, pollakisuria, weight gain, sleepiness, dizziness, decreased libido and mild breast tenderness or swelling.
Current standard treatment of oophorectomized women calls for administration of an estrogen, or an estrogen and an androgen. Typical treatment protocols have involved the administration of: an oral estrogen alone (such as conjugated estrogens or esterified estrogens) or with an oral androgen (such as methyltestosterone); transdermal estrogen (such as estradiol); and injectable pellets of estrogen alone, or with testosterone [Stanczyk, F. Z. et al., "A randomized comparison of nonoral estradiol delivery in postmenopausal women," Am. J. Obstet. Gynecol. 159: 1540-6 (1988); Chetkowski, R. J. et al., "Biologic effects of transdermal estradiol," N. Engl. J. Med. 314: 1615-20 (1986); Ralston, S. H. et al., "Effect of subdermal estrogen and estrogen/testosterone implants on calcium and phosphorus homeostasis after oophorectomy," Maturitas 6: 341-44 (1984)].
Androgens have been administered in these settings to improve sexual functioning, but there are significant negative effects. The administration of even a low dose (e.g., 1.25 to 2.5 mg) of an oral androgen, such as methyltestosterone, with oral estrogens is associated with detrimental changes in blood cholesterol patterns [Notelovitz, M. et al., "Influence of extended treatment with oral estrogens/androgen combination on lipids and lipoproteins in surgically menopausal women," North American Menopause Society, 1991, Meeting Abstract S-B5 (Montreal, Canada 1991); Youngs, D. D. & Sherwin, B. B., "Effects of an oral estrogen-androgen preparation on lipoprotein lipids in postmenopausal women: a pilot study," North American Menopause Society, 1991, Meeting Abstract P-130 (Montreal, Canada 1991). The addition of testosterone implants to estrogen appears to have only a small impact on cholesterol patterns. While it may negate the positive beneficial effects of the estrogen on cholesterol, a detrimental effect is not clearly seen [Farish, E. et al., "The effects of hormone implants on serum lipoproteins and steroid hormones in bilaterally oophorectomized women," Acta Endocrinologica 106: 116-20 (1984)].
The use of pellets of testosterone unfortunately results in large variations in serum levels of testosterone over time. High levels are observed shortly after administration [Burger, H. G. et al, "The management of persistent menopausal symptoms with estradiol-testosterone implants: clinical, lipid and hormonal results," Maturitas 6: 351-8 (1984)]. Elevated serum testosterone levels with associated virilization or masculinization can occur with repeated administration, if caution is not used [Urman, B. et al., "Elevated serum testosterone, hirsutism, and virilism associated with combined androgen-estrogen hormone replacement therapy," Obstet. Gynecol. 77: 595-8 (1991)]. Further, the serum testosterone levels achieved with such approaches may be substantially above usual levels is normal premenopausal women [Sherwin, B. B. et al., "Postmenopausal estrogen and androgen replacement and lipoprotein lipid concentrations," Am. J. Obstet. Gynecol. 156: 414-9 (1987)].
It has generally been assumed that treatment of oophorectomized women with low-dose estrogen, such as 0.625 mg of oral conjugated estrogens, will prevent any loss of bone mineral density (BMD) [Genant, H. et al., "Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy," Ann. Intern. Med. 97: 699-705 (1982)]. Recent clinical studies on women with a medical oophorectomy (induced by a gonadotropin releasing hormone agonist, GnRHA) have clearly shown that this is incorrect, and that a conventional oral dose of 0.625 to 0.9 mg of conjugated estrogens is inadequate. While higher doses of estrogens may be employed to prevent loss of BMD, exogenous estrogen is associated with a significant increase in the risk of breast cancer. This is a dose-dependent effect, so that the lowest possible dose of estrogen to prevent adverse symptoms is desirable.
Preliminary results with the addition of a small dose of oral replacement androgen (1.25 to 2.5 mg of methyltestosterone) to the GnRHA plus conjugated estrogens regimen show protection against the loss of BMD. Unfortunately, the addition of the methyltestosterone has produced detrimental changes in serum cholesterol as noted previously.
It is an object of the present invention to provide methods and formulations which are useful in long-term treatment of oophorectomized women and women with other forms of ovarian failure.